Pathogen-associated molecular patterns (PAMPs), are molecules associated with groups of pathogens that are recognized by cells of the innate immune system. These molecules can be referred to as small molecular motifs conserved within a class of microbes. They are recognized by “Toll-like receptor” (TLRs) and other “Pattern recognition receptor” (PRRs) in both plants and animals. They activate innate immune responses, protecting the host from infection, by identifying some conserved non-self molecules. Bacterial Lipopolysaccharide (LPS) found on the bacterial cell membrane of a bacterium, is considered to be the prototypical PAMP. LPS is specifically recognized by a recognition receptor of the innate immune system. Other PAMPs include bacterial Flagellin, Lipoteichoic acid from gram-positive bacteria, peptidoglycans (PGs), and nucleic acid variants normally associated with viruses, such as double-stranded RNA recognized by TLR 3 or unmethylated CpG motifs, recognized by TLR 9. Although the term “PAMP” is relatively new, the concept that molecules derived from microbes must be detected by receptors from multicellular organisms has been held for many decades.
Lipopolysaccharides are part of the outer membrane of the cell wall of gram-negative bacteria. Lipopolysaccharides are invariably associated with gram-negative bacteria whether the organisms are pathogenic or not. Endotoxin generally refers to the lipopolysaccharide complex associated with the outer membrane of gram-negative pathogens such as Escherichia coli, Salmonella, Shigella, Pseudomonas, Neisseria, Haemophilus influenzae, Bordetella pertussis and Vibrio cholerae. The term “endotoxin” is occasionally used to refer to any cell-associated bacterial toxin. While endotoxin refers to cell associated lipopolysaccharides, exotoxin refers to toxins secreted by bacteria and are predominantly polypeptides in nature.
The biological activity of endotoxin is associated with the lipopolysaccharide (LPS). Toxicity is associated with the lipid component (Lipid A) and immunogenicity is associated with the polysaccharide components. The cell wall antigens (O antigens) of gram-negative bacteria are the polysaccharide components of LPS. In addition, LPS can elicit a variety of inflammatory responses in an animal.
Gram-negative bacteria, within animals, probably release minute amounts of endotoxin while growing. This may be important in the stimulation of natural immunity. It is known that small amounts of endotoxin may be released in a soluble form by young cultures grown in the laboratory. But for the most part, endotoxins remain associated with the cell wall until disintegration of the organisms. Disintegration of the bacterial organisms can result from autolysis, external lysis mediated by complement and lysozyme, and phagocytic digestion of bacterial cells. Bacterial endotoxin is abundant in the human gut. Elevated concentrations of endotoxins are associated with a number of conditions including metabolic syndrome. Metabolic syndrome diseases include, for example, artherosclorosis, insulin resistance, diabetes mellitus, and obesity. Increased endotoxin levels have also been associated with fatty liver disease and Crohn's disease. Endotoxin may also leak out of the GI tract when present at elevated levels. Endotoxin is a potent inflammatory antigen and leaking of the endotoxin can result in systemic inflammatory response.
Compared to the classic exotoxins of bacteria, endotoxins are less potent and less specific in their action, since they do not act enzymatically. Endotoxins are heat stable (boiling for 30 minutes does not destabilize endotoxin), but certain powerful oxidizing agents such as superoxide, peroxide and hypochlorite, have been reported to neutralize them. Since these are powerful oxidizing agents they are not particularly amenable to a therapeutic composition for neutralizing endotoxins.
There are a number of other molecules that can also act as bacterial toxins. Gram-negative bacteria can also produce a number of other toxins such as Shiga toxin and leukotoxin. These may be associated with the cells or they may also be secreted by the cells into the extracellular space. Peptidoglycans are also associated with bacteria, especially gram-positive bacteria. The peptidoglycan layer in gram-positive bacteria is substantially thicker than in gram-negative bacteria. The peptidoglycan layer is about nine times thicker in gram-positive bacteria than in gram-negative bacteria. Peptidoglycans are associated with cell walls. Capsular polysaccharides are another bacterial component associated with the cells in both gram-positive and gram-negative bacteria.